Renal cell carcinoma is a devastating cancer affecting 36,600 individuals per year in the US and rising steadily in incidence, but with few effective treatments. Mutations in the von Hippel-Lindau (VHL) gene have been associated with the majority of sporadic cancers of the kidney, and with the hereditary syndrome of VHL disease in which mutational carriers are at risk for development of renal cell carcinoma, as well as hemangioblastoma of the nervous system, and pheochromocytoma. Individual missense mutations predispose predictably to the penetrance of each of these tumors. VHL protein (pVHL) has been implicated in many activities, most notably the oxygen dependent regulation of the hypoxia inducible factors HIF1-alpha and HIF2-alpha which trancriptionally regulation a large cohort of hypoxia response genes. However, other activities of pVHL are also tumor-promoting, as missense mutations associated with exclusively pheochromocytoma have no effect on regulation of hypoxia response genes. VHL mutation, however, is implicated early in the pathway of tumorigenesis of the kidney, likely playing a tumor-initiating role. The mutations which augment the development of invasive renal cell carcinoma are not well-understood, and may contribute to the refractoriness of this tumor to conventional therapies. Understanding the complete spectrum of carcinogenic activities of VHL loss as well as the cellular events which supplement tumor progression in the kidney is an essential goal in a mission to improve treatments for renal cell carcinoma. This proposal outlines an integrated and balanced approach to meeting this goal by developing in vitro and in vivo models of VHL mutations associated with the complete spectrum of VHL disease, and exploiting the strong genotype:phenotype correlation of VHL disease in a mouse model system. Additionally, we propose a strategy to induce somatic loss of VHL in the kidney tubule to model VHL initiation of renal carcinogenesis, as well as somatic activation of putative renal tumor "progression" pathways in a background of VHL mutation. These investigations will provide a unique model system in which many aspects of VHL-induced carcinogenesis can and will be examined in order to ultimately identify improved treatments for patients with renal cell carcinoma.